Androgens Rapidly Activate Nuclear Factor-Kappa B via Intracellular Ca2+ Signalling in Human Vascular Endothelial CellsMcGrath KCY1,2, Li XH2, Gaus K3, Williams P4, Celermajer DS2,4,5, Handelsman DJ4,6 and Heather AK1,2*
- Corresponding Author:
- Dr. Alison Heather
University of Technology Sydney
PO Box 123, Broadway, Ultimo
NSW, 2007, Australia
Fax: 612- 9565-5584
E-mail: [email protected]
Received Date: January 03, 2012; Accepted Date: February 22, 2012; Published Date: February 25, 2012
Citation: McGrath KCY, Li XH, Gaus K, Williams P, Celermajer DS et al. (2012) Androgens Rapidly Activate Nuclear Factor-Kappa B via Intracellular Ca2+ Signalling in Human Vascular Endothelial Cells. J Steroids Hormon Sci S2:005. doi: 10.4172/2157-7536.S2-005
Copyright: © 2012 McGrath KCY, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
There exists a striking gender difference in the incidence of atherosclerosis. Androgen exposure may predispose men to earlier onset atherosclerosis. We previously demonstrated that the potent androgen, dihydrotestosterone, enhanced the binding of monocytes to endothelial cells, via androgen receptor/nuclear factor kappa B-dependent expression of the cell adhesion molecules, vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1. We now show that testosterone and dihydrotestosterone can also induce a novel, non-genomic pathway that leads to the rapid activation of nuclear factor-kappa B via intracellular Ca2+ signalling, initiated at the plasma membrane. Human umbilical vein endothelial cells exposed to 6-60 nM testosterone or dihydrotestosterone showed a rapid increase in intracellular calcium levels. The testosterone or dihydrotestosterone effect on increased intracellular calcium could not be abrogated by pre-incubation with androgen receptor antagonist, hydroxyflutamide, or by U73122, an inhibitor of intracellular calcium release from endoplasmic reticulum stores. However, pre-incubation with both Ni2+or an extracellular Ca2+ chelator blocked the testosterone-induced intracellular Ca2+ surge. Testosterone conjugated to bovine serum albumin was equal to free testosterone in its ability to induce the intracellular Ca2+ surge. Binding studies showed testosterone does bind to the plasma membrane, however, classical androgen receptor was unable to be detected in the plasma membrane of human umbilical vein endothelial cells. Testosterone was found to rapidly increase nuclear factor-kappa B activity, an effect that was blocked when cells were incubated in calcium-free media. This study demonstrates for the first time that testosterone induces a non-genomic membrane-initiated Ca2+ dependent signalling pathway that leads to the rapid activation of nuclear factor-kappa B.